Biomaterial-assisted electroporation: Comparing design principles for gene delivery and local tumor therapy
Background: From opening cell membranes to therapeutic delivery
Biomaterial-assisted electroporation is evolving toward designs that jointly address payload protection, electric-field control, and drug retention at the treatment site. A review published in Small compares the roles and limitations of approaches using nanoparticles, hydrogels, and micro- and nanoelectrodes. It synthesizes prior studies in gene delivery, tumor ablation, and immune modulation rather than reporting experiments on a single new platform.
Electroporation changes cell-membrane permeability with brief electrical pulses. Reversible electroporation (RE) creates temporary hydrophilic nanopores that allow nucleic acids, proteins, and drugs to enter cells, with conditions adjusted so the membrane recovers after the pulses end. Irreversible electroporation (IRE), by contrast, aims for nonthermal tissue ablation through permanent membrane damage. Keeping cells alive to deliver materials and removing cells have different therapeutic goals.
With conventional approaches, nonuniform electric fields can leave some areas within the same target insufficiently stimulated and others excessively stimulated. Sensitive cells may also show reduced survival and function after strong pulses. The review explains that opening the membrane alone does not ensure protection of unstable payloads or prolonged retention at the treatment site.
Key findings: Different materials address different delivery barriers
The review presents design principles for selecting materials according to therapeutic bottlenecks. Micro- and nanoelectrodes concentrate the electric field in small areas in contact with cell membranes to improve the spatial precision of delivery. This approach is promising for ex vivo genetic engineering of sensitive immune cells or stem cells, but complex fabrication and scaling up throughput remain challenges.
The main roles of nanoparticles and liposomes are to protect nucleic acids or proteins, carry multiple payloads together, and help them accumulate at target sites. Strong electrical pulses, however, can destabilize carriers or alter release patterns, so compatibility between the material and pulse conditions must be tested together. Biodistribution, clearance, and the potential for oxidative stress also need assessment.
Hydrogels serve as reservoirs that retain drugs at the treatment site and release them over time, as well as soft interfaces for tissue contact. Examples include locally delivering immunomodulatory agents after tumor ablation or bringing electrodes into close contact with irregular tissue surfaces. Limitations include the burden of invasive procedures for placement in deep tissue, degradation, swelling, changes in conductivity, and long-term inflammation.
No material is always superior. The appropriate combination depends on which factor is the bottleneck: precision of local membrane permeabilization, payload stability, or retention time at the treatment site.
Implications and outlook: Beyond delivery efficiency to reproducibility and long-term function
The authors note that performance cannot be explained by voltage and pulse count alone. Electrode spacing and geometry, tissue conductivity, material properties, temperature, and electrochemical changes all contribute to biological outcomes. The nonthermal operating principle of IRE does not eliminate risks such as electrothermal injury, edema, inflammation, or electrode-related damage.
For cell manufacturing, the proposed evaluation criteria include delivery efficiency immediately after treatment, survival, proliferation, long-term function, and consistency between batches. In local tumor therapy, strategies are being considered to align drug release with immune changes after ablation. No universally optimal schedule has been established, and success with local treatment alone cannot guarantee control of metastatic cancer throughout the body.
The review proposes jointly designing materials, electrical pulses, and electrode structures. Practical application will require evaluating manufacturing scalability, long-term safety, the burden of additional procedures, and regulatory requirements for combination products. The comparative evidence and remaining challenges are summarized in the full review.
Electroporation has evolved from a membrane-permeabilization method into a versatile therapeutic platform for intracellular delivery, locoregional tumor intervention, and bioelectrically regulated treatment. Depending on pulse intensity and duration, electroporation operates in two distinct modes: reversible electroporation (RE), which transiently permeabilizes the plasma membrane to enable delivery of nucleic acids, proteins, and small molecules while preserving cell viability, and irreversible electroporation (IRE), which causes permanent membrane damage for non-thermal tissue ablation. Increasingly, the therapeutic scope of electroporation is being expanded through integration with biomaterials, including nanocarriers, hydrogels, soft conductors, and micro/nanoengineered bioelectronic interfaces. These material-assisted strategies improve cargo protection, field confinement, local retention, tissue conformity, and spatiotemporal control, thereby extending electroporation beyond conventional transfection toward gene editing, engineered cell manufacturing, electrochemotherapy, tumor ablation, immune modulation, and transdermal or localized delivery. In this Review, we summarize the biophysical principles of RE and IRE, discuss how biomaterials reshape electroporation performance across therapeutic settings, compare the design logic of major biomaterial-assisted electroporation platforms, and highlight key translational challenges, including pulse-material compatibility, manufacturing scalability, in vivo dosimetry, and regulatory complexity.
Researchers manipulating immune cells or stem cells ex vivo need to assess delivery efficiency alongside cell function after treatment. Even if micro- or nanoelectrodes improve the precision of local delivery, researchers must still verify that cells retain their ability to proliferate and function while achieving the required production volume. This review provides evaluation criteria for comparing materials and devices.
For local tumor therapy, one scenario to consider is loading drugs and immunomodulatory agents into a hydrogel or injectable reservoir to retain them at the ablation site and control release timing. Material placement may require an additional procedure, so the benefits must be weighed against procedural burden and long-term safety. The review itself does not establish treatment efficacy in patients for any particular combination or demonstrate accelerated regulatory approval.